prostaglandin-d2 and Leukemia--Myeloid

Members of the aldo-keto reductase (AKR) superfamily, particularly the AKR1C subfamily, are emerging as important mediators of the pathology of cancer. Agents that inhibit these enzymes may provide novel agents for either the chemoprevention or treatment of diverse malignancies. Recently, jasmonates, a family of plant stress hormones that bear a structural resemblance to prostaglandins, have been shown to elicit anticancer activities both in vitro and in vivo. In this study, we show that jasmonic acid (JA) and methyl jasmonate (MeJ) are capable of inhibiting all four human AKR1C isoforms. Although JA is the more potent inhibitor of recombinant AKR1C proteins, including the in vitro prostaglandin F synthase activity of AKR1C3, MeJ displayed greater potency in cellular systems that was, at least in part, due to increased cellular uptake of MeJ. Moreover, using the acute myelogenous leukemia cell lines HL-60 and KG1a, we found that although both jasmonates were able to induce high levels of reactive oxygen species in a dose-dependent fashion, only MeJ was able to induce high levels of mitochondrial superoxide (MSO), possibly as an epiphenomenon of mitochondrial damage. There was a strong correlation observed between MSO formation at 24 hours and reduced cellularity at day 5. In conclusion, we have identified AKR1C isoforms as a novel target of jasmonates in cancer cells and provide further evidence of the promise of these compounds, or derivatives thereof, as adjunctive therapies in the treatment of cancer.

Topics: 20-Hydroxysteroid Dehydrogenases; Acetates; Cell Survival; Cells, Cultured; Cyclopentanes; Drug Delivery Systems; Drug Evaluation, Preclinical; Enzyme Inhibitors; HL-60 Cells; Humans; Hydroxyprostaglandin Dehydrogenases; Isoenzymes; Leukemia, Myeloid; Mitochondria; Models, Biological; Oxylipins; Prostaglandin D2; Reactive Oxygen Species

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is one of the best characterized nuclear hormone receptors (NHRs) in the superfamily of ligand-activated transcriptional factors. PPAR-gamma ligands have recently been demonstrated to affect proliferation, differentiation and apoptosis of different cell types. The present study was undertaken to investigate PPAR-gamma ligands induced cell growth inhibition and its influence on matrix metalloproteinase MMP-9 and MMP-2 activities on leukemia K562 and HL-60 cells in vitro. The results revealed that PPAR-gamma expression was detectable in the two kinds of leukemia cells; Both 15-deoxy-delta(12,14)-prostaglandin J2(15d-PGJ2) and troglitazone (TGZ) have significant growth inhibition effects on these two kinds of leukemia cells. These two PPAR-gamma ligands could inhibit the leukemic cell adhesion to the extracellular matrix (ECM) proteins and the invasion through matrigel matrix. The expressions of MMP-9 and MMP-2 as well as their gelatinolytic activities in both HL-60 and K562 cells were inhibited by 15d-PGJ2 and TGZ significantly. We therefore conclude that PPAR-gamma ligands 15d-PGJ2 and TGZ have significant growth inhibition effects on myeloid leukemia cells in vitro, and that PPAR-gamma ligands can inhibit K562 and HL-60 cell adhesion to and invasion through ECM as well as downregulate MMP-9 and MMP-2 expressions. The data suggest that PPAR-gamma ligands may serve as potential anti-leukemia reagents.

Topics: Antineoplastic Agents; Chromans; Extracellular Matrix; Humans; Leukemia, Myeloid; Metalloproteases; PPAR gamma; Prostaglandin D2; Thiazolidinediones; Troglitazone; Tumor Cells, Cultured

delta 12-prostaglandin J2 (PGJ2) is a dehydration product of PGD2 and thought to be the most potent antitumor agent among prostaglandin compounds. We examine the cytotoxic effects of PGJ2 on the cell growth of leukemia/lymphoma cells. PGJ2 inhibited the growth of both human PL-21 myeloid leukemia and RC-K8 pre-B lymphoma cells in culture in a dose-dependent manner with fragmentation of nucleus and formation of apoptotic body. Agarose gel electrophoresis revealed DNA ladder formation in the cells treated with PGJ2. Furthermore, PGJ2 induced a rapid and transient expression of apoptosis-related protooncogene, c-fos, in both cells. The gene transcriptional rate was remarkably increased approximately 3.3-fold in PGJ2 treated cells, but the stability of c-fos mRNA was not significantly changed. Inhibition of de novo protein synthesis with cycloheximide increased c-fos mRNA stability but not abrogated PGJ2-induced c-fos transcription. These data suggest that PGJ2 can induce apoptosis of human leukemia/lymphoma cells and the rapid activation of c-fos protooncogene transcription in which de novo protein synthesis is not required.

Topics: Antineoplastic Agents; Apoptosis; Cell Division; DNA Fragmentation; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid; Lymphoma, B-Cell; Prostaglandin D2; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-fos; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured